Correspondence
Strategies to Improve Outcomes after Renal Transplantation
N Engl J Med 2002; 346:2089-2092June 27, 2002
- Article
To the Editor:
Like most reviews of strategies to improve outcomes in recipients of renal transplants, the recent article by Pascual et al. (Feb. 21 issue)1 focused on immunologic issues and immunosuppression. It is becoming clear, however, that the most common cause of graft loss is death (due to cardiovascular disease in 30 to 50 percent of cases) and that most chronic graft loss is nonimmunologic.2 Pascual et al., in fact, concede these points. It stands to reason that aggressive treatment of nonimmunologic causes of graft failure and cardiovascular disease might have a larger effect in renal-transplant recipients than any type of immunosuppression.
Most patients with renal transplants have mild-to-moderate chronic renal insufficiency. As in patients with chronic renal insufficiency from other causes, hypertension is prevalent in renal-transplant recipients and is associated with graft loss, congestive heart failure, ischemic heart disease, and death.3,4 Anemia, present in 15 to 25 percent of renal-transplant recipients, is a risk factor for left ventricular enlargement, congestive heart failure, and death.4 Diabetes, smoking, hyperlipidemia, and hyperhomocysteinemia all have adverse cardiac and renal consequences, as they do in patients with chronic renal insufficiency and those receiving dialysis.4,5 In short, aggressive blood-pressure control, early use of angiotensin-converting–enzyme inhibitors, aggressive management of anemia, aggressive lipid control, tight control of diabetes, and lowering of homocysteine levels are likely to have a profound effect on the outcomes of transplantation and should be addressed in clinical trials.
5 ReferencesClaudio Rigatto, M.D.
University of Manitoba, Winnipeg, MB R2H 2A6, Canada
crigatto@sbgh.mb. ca Patrick Parfrey, M.D.
Memorial University of Newfoundland, St. John's, NF A1B 3V6, Canada1
Pascual M ,Theruvath T ,Kawai T ,Tolkoff-Rubin N ,Cosimi AB . Strategies to improve long-term outcomes after renal transplantation. N Engl J Med 2002;346:580-590
Full Text | Web of Science | Medline2
Halloran P ,Melk A ,Barth C . Rethinking chronic allograft nephropathy: the concept of accelerated senescence. J Am Soc Nephrol 1999;10:167-181
Web of Science | Medline3
Rigatto C ,Parfrey P ,Foley R ,Negrijn C ,Tribula C ,Jeffery J . Congestive heart failure in renal transplant recipients: risk factors, outcomes, and relationship with ischemic heart disease. J Am Soc Nephrol 2002;13:1084-1090
Web of Science | Medline4
Kasiske BL ,Guijarro C ,Massy ZA ,Wiederkehr MR ,Ma JZ . Cardiovascular disease after renal transplantation. J Am Soc Nephrol 1996;7:158-165
Web of Science | Medline5
Ducloux D ,Motte G ,Challier B ,Gibey R ,Chalopin JM . Serum total homocysteine and cardiovascular disease occurrence in chronic, stable renal transplant recipients: a prospective study. J Am Soc Nephrol 2000;11:134-137
Web of Science | Medline
To the Editor:
Pascual et al. list strategies for preventing long-term complications in renal-transplant recipients. We would like to add to this list the prevention and control of post-transplantation diabetes mellitus.
In a systematic review of 19 published studies, including data on 3611 transplant recipients,1 we identified age, nonwhite race, and episodes of rejection as risk factors for post-transplantation diabetes mellitus. According to a meta-regression analysis, however, the choice of immunosuppressive regimen explained 74 percent of the variation in the 12-month cumulative incidence of post-transplantation diabetes mellitus (P<0.001). The use of high doses of prednisone, cyclosporine, and tacrolimus was responsible for this strong association. Although post-transplantation diabetes mellitus was associated with an increased risk of severe infections, its effect on cardiovascular outcomes and graft survival was unclear.
The limited incidence of post-transplantation diabetes mellitus in published randomized trials of sirolimus and azathioprine2,3 may support their preferential use in patients at high risk for post-transplantation diabetes mellitus. Strict glycemic control after transplantation awaits proof of efficacy and safety. Meanwhile, these strategies and others listed by Pascual et al. promise to decrease the burden of long-term complications after renal transplantation.
3 ReferencesVictor M. Montori, M.D.
Ananda Basu, M.D.
Yogish C. Kudva, M.D.
Mayo Clinic Rochester, Rochester, MN 55905
montori.victor@mayo. edu 1
Montori VM ,Basu A ,Erwin PJ ,Velosa JA ,Gabriel SE ,Kudva YC . Posttransplantation diabetes: a systematic review of the literature. Diabetes Care 2002;25:583-592
CrossRef | Web of Science | Medline2
MacDonald AS, RAPAMUNE Global Study Group
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Kahan BD . Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. Lancet 2000;356:194-202
CrossRef | Web of Science | Medline
To the Editor:
Pascual et al. discuss the effect of cardiovascular disease on the survival of renal grafts and renal-transplant recipients and allude to the benefits of pharmacologic management of risk factors for cardiovascular disease. In our opinion, the treatment of renal-transplant recipients must also include attention to cultural, socioeconomic, and lifestyle factors — for example, diet, physical activity, and eating-related behavior. Organ transplantation is associated with accelerated atherogenesis due to the cumulative effects of preexistent vascular disease and the combined effect of environmental factors and immunosuppressive medications on the risk of cardiovascular disease.1 Recent data indicate that black renal-transplant recipients have a greater risk than white recipients of weight gain and diabetes after transplantation,2 as well as a risk of graft failure that is 1.8 times as high as that of white recipients.3 To some extent, this disparity in outcome reflects a higher prevalence of risk factors for cardiovascular disease in black patients4 and indicates the need for greater awareness of obesogenic and diabetogenic lifestyle factors in this population. Aggressive lifestyle management in the form of modification of diet, management of weight, physical activity, and attention to socioeconomic factors should be routine components of any attempt to modify cardiovascular risk.
4 ReferencesCharles L. Baum, M.D.
Anastasia P. McGee, R.D.
University of Illinois Medical Center, Chicago, IL 60612
baum@uic.edu 1
Baum CL . Weight gain and cardiovascular risk after organ transplantation. JPEN J Parenter Enteral Nutr 2001;25:114-119
CrossRef | Web of Science | Medline2
Baum CL ,Thielke K ,Westin E ,Kogan E ,Cicalese L ,Benedetti E . Predictors of weight gain and cardiovascular risk in a cohort of racially diverse kidney transplant recipients. Nutrition 2002;18:139-146
CrossRef | Web of Science | Medline3
Isaacs RB ,Nock SL ,Spencer CE , et al. Racial disparities in renal transplant outcomes. Am J Kidney Dis 1999;34:706-712
CrossRef | Web of Science | Medline4
Ofili E . Ethnic disparities in cardiovascular health. Ethn Dis 2001;11:838-840
Medline
To the Editor:
In their review of strategies to improve long-term outcomes of renal transplantation, Pascual and colleagues suggest that lowering cyclosporine doses may, among other things, lead to a reduction in total plasma levels of the putative atherothrombotic risk factor homocysteine. In support of this theory, they refer to a cross-sectional study by Arnadottir et al.1 that found that renal-transplant recipients receiving cyclosporine-based regimens had significantly higher plasma total homocysteine levels than those not receiving cyclosporine. Unfortunately, this study did not adjust for differences between groups in the glomerular filtration rate, the primary determinant of plasma total homocysteine levels.2,3 Subsequent studies of renal-transplant recipients that identified determinants of total homocysteine levels and that adjusted for all major potential confounders, including renal function, found no relation between plasma total homocysteine levels and cyclosporine use.3,4
Fasting hyperhomocysteinemia has been shown to be an independent predictor of cardiovascular events among renal-transplant recipients.4 This finding is of particular importance because such patients have a much higher prevalence of hyperhomocysteinemia3,4 than the general population, as well as a dramatically increased risk of cardiovascular disease and death from cardiovascular causes.4 In the process of elucidating the causes of hyperhomocysteinemia in renal-transplant recipients, it is obviously important to avoid erroneously implicating factors that may have very useful effects. Although there are numerous advantages to lowering cyclosporine doses in renal-transplant recipients, including improved renal hemodynamics and function, blood-pressure control, and normalization of metabolic derangements, reducing total homocysteine levels does not appear to be among them.
4 ReferencesAllon Friedman, M.D.
Tufts University, Boston, MA 02111
afriedman@hnrc.tufts. edu 1
Arnadottir M ,Hultberg B ,Vladov V ,Nilsson-Ehle P ,Thysell H . Hyperhomocysteinemia in cyclosporine-treated renal-transplant recipients. Transplantation 1996;61:509-512
CrossRef | Web of Science | Medline2
Arnadottir M ,Hultberg B ,Nilsson-Ehle P ,Thysell H . The effect of reduced glomerular filtration rate on plasma total homocysteine concentration. Scand J Clin Lab Invest 1996;56:41-46
CrossRef | Web of Science | Medline3
Bostom AG ,Gohh RY ,Beaulieu AJ , et al. Determinants of fasting plasma total homocysteine levels among chronic stable renal transplant recipients. Transplantation 1999;68:257-261
CrossRef | Web of Science | Medline4
Ducloux D ,Motte G ,Challier B ,Gibey R ,Chalopin JM . Serum total homocysteine and cardiovascular disease occurrence in chronic, stable renal transplant recipients: a prospective study. J Am Soc Nephrol 2000;11:134-137
Web of Science | Medline
To the Editor:
Pascual et al. focus exclusively on pharmacologic and immunologic approaches to achieving long-term survival of grafts and patients after renal transplantation, without acknowledging that noncompliance of patients with these expensive and elaborate strategies is an important source of failure. Because they are difficult to assess, the rates of noncompliance with immunosuppressive regimens after transplantation are most likely underestimated, given studies that show that an average of 18 percent of patients skipped their daily dose of azathioprine for 4 or more days within the first 6 months1 and that by 12 months, the rate of compliance with a multidrug immunosuppressive regimen, provided free of charge, was only 48 percent (with compliance determined by the refill rate for prescriptions).2 Overt noncompliance was recognized as the cause of 10 percent of graft losses among 653 renal-transplant patients with a first episode or multiple episodes of acute rejection after the first year after transplantation.3 Noncompliance-induced graft loss is now encountered with sufficient frequency to provoke academic debate over whether such patients should be afforded the opportunity to receive another kidney transplant.4
4 ReferencesAmy Friedman, M.D.
Yale University School of Medicine, New Haven, CT 06520
amy.friedman@yale. edu 1
Nevins TE ,Kruse L ,Skeans MA ,Thomas W . The natural history of azathioprine compliance after renal transplantation. Kidney Int 2002;60:1565-1570
CrossRef | Web of Science2
Chisholm M ,Vollenweider LJ ,Mulloy LL , et al. Renal transplant patient compliance with free immunosuppressive medications. Transplantation 2000;70:1240-1244
CrossRef | Web of Science | Medline3
Matas AJ ,Gillingham KJ ,Payne WD ,Najarian JS . The impact of an acute rejection episode on long-term renal allograft survival (t1/2). Transplantation 1994;57:857-859
CrossRef | Web of Science | Medline4
Troppmann C ,Benedetti E ,Gruessner RW ,Najarian JS ,Matas AJ . Should patients with renal allograft loss due to noncompliance be retransplanted? Transplant Proc 1995;27:1093-1093
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Drs. Rigatto and Parfrey that as immunosuppressive regimens have become more effective, it has become apparent that increased attention must be paid to nonimmunologic causes of renal-allograft failure. However, it should also be acknowledged that many of the allograft losses due to nonimmunologic causes result, at least in part, from the side effects of the drugs that must be administered to control the recipient's immunologic responses. An important goal of current approaches, therefore, is not only to provide safe and adequate immunosuppression to control the anti-allograft response, but also to minimize atherosclerotic risk factors and nephrotoxic effects of the drugs. Optimal control of hypertension and hyperlipidemia is indeed critical. Whether “aggressive management of anemia, . . . tight control of diabetes, and lowering of homocysteine levels” will have a larger effect on the outcomes of transplantation than any type of immunosuppression, however, remains to be validated in prospective clinical trials.
Montori and colleagues emphasize that prevention and appropriate control of post-transplantation diabetes mellitus are also important issues that we did not discuss in detail because of space constraints. In patients at risk for post-transplantation diabetes mellitus, regimens incorporating immunosuppressive drugs that do not have diabetogenic effects or that do not include corticosteroids are also attractive options, with the caveats that we mention in our article. In addition, as Baum and McGee note, lifestyle, socioeconomic, and cultural factors may be neglected after transplantation. Attention to these factors (especially weight management) should indeed be beneficial and improve the outcomes of transplantation. A multidisciplinary-team approach, involving not only transplantation doctors and nurses but also social workers, psychiatrists, and dietitians, is often necessary to optimize these aspects of treatment.
We agree with Dr. Allon Friedman that the glomerular filtration rate is the primary determinant of plasma total homocysteine levels, although the precise mechanisms of the development of hyperhomocysteinemia in patients with chronic renal dysfunction are incompletely understood.1 We have only suggested that, in patients who are in stable condition after the first 6 to 12 months after transplantation, serum levels of homocysteine may decrease after a reduction in the dose of cyclosporine because of the improvement in the glomerular filtration rate that can be anticipated if rejection does not occur. We did not imply that cyclosporine use had a direct effect on plasma homocysteine levels.
Finally, as Dr. Amy Friedman correctly points out, the problem of noncompliance after transplantation is difficult to assess and thus may be underestimated. As illustrated in our review, noncompliance can result in acute rejection and late graft loss (Figure 2 of the article), but it may also lead to a subacute and chronic alloimmune response, contributing to the development of chronic allograft nephropathy by means of immunologic mechanisms (Figure 3 and Figure 4).
1 ReferencesManuel Pascual, M.D.
Nina Tolkoff-Rubin, M.D.
A. Benedict Cosimi, M.D.
Massachusetts General Hospital, Boston, MA 02114
mpascual@partners.org 1
Friedman AN ,Bostom AG ,Selhub J ,Levey AS ,Rosenberg IH . The kidney and homocysteine metabolism. J Am Soc Nephrol 2001;12:2181-2189
Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
M. Lorenz, W. C. Winkelmayer, W. H. Horl, G. Sunder-Plassmann. (2005) Anaemia after renal transplantation. European Journal of Clinical Investigation 35:s3, 89-94
CrossRef
